The present invention relates to a new pharmaceutical composition and method for use as a treatment of human immunodeficiency virus (xe2x80x9cHIVxe2x80x9d), as well as for secondary microbial infections and inflammation in persons with HIV. More particularly, this invention relates to a tripeptide sequence contained in alpha-melanocyte stimulating hormone (xe2x80x9calpha-MSHxe2x80x9d), which has been identified as an antiviral, antibacterial, antifungal and anti-inflammatory agent.
HIV is a virus that weakens the immune system through destruction of lymphocytes. Because thousands of people die each year from HIV, the need for treatment of the virus, as well as secondary infections, is significant. HIV is considered to be a member of the lentivirus family of animal retroviruses on the basis of genomic sequence homologies, morphology and life cycle. Lentiviruses are capable of long-term latent infection, infection of cells or short-term cytopathic effects, and they all produce slowly progressive, fatal diseases. Both humoral and cell-mediated immune responses specific for a wide variety of HIV gene products have been observed in HIV-infected patients. Given the high fatality rate among HIV-infected individuals, it is clear that these immune responses to the viruses do not confer adequate protection. Because of the complex biology of HIV, the clinical manifestations of infection are quite variable. Persons with HIV frequently become infected with Staphylococcus aureus and Candida albicans. 
S. aureus organisms are pyogenic, nonmotile, gram-positive cocci that tend form grape-like clusters. Staphylococci cause a myriad of skin lesions, such as boils, carbuncles, impetigo and scalded skin. Staphylococci also cause pharymgitis, pneumonia, endocarditis, food poisoning and toxic shock syndrome. S. aureus is the major cause of infection of patients with severe burns and surgical wounds and is second only to E. coli as a cause of hospital-acquired infections.
S. aureus possesses a multitude of virulence factors, which includes surface proteins involved in adherence to host cells, secreted enzymes that degrade host proteins, and secreted toxins that damage host cells. S. aureus has, on its surface, receptors for fibrinogen, fibronectin, and vitronectin and uses these molecules as a bridge to bind to host endothelial cells.
S. aureus has a laminin receptor which is similar to metastatic tumor cells and allows bacteria to bind to host extracellular matrix proteins and invade host tissues.
Staphylococci infecting prosthetic valves and catheters have an exopolysaccharide capsule that allows them to attach to the artificial materials and to resist host cell phagocytosis.
The lipase of S. aureus degrades lipids on the skin surface, and its expression is correlated with the ability of the bacteria to produce skin abscesses.
S. aureus produces multiple hemolytic toxins, including alpha toxin, which is a pore-forming protein that intercalates into the plasma membrane of host cells and depolarizes them; betatoxin, a sphingomyelinase; and delta-toxin, which is an anphipathic (detergent-like) peptide.
S. aureus enterotoxins are associated with food poisoning and appear to act by stimulating emetic receptors in the abdominal viscera to cause vomiting and diarrhea. In addition, S. aureus enterotoxins are superantigens. They bind to macrophage major histocompatibility complex (MHC) class II molecules at a conserved site away from the hypervariable groove and then to the site of the T-cell receptor beta chain, rather than to its variable face that recognizes conventionally processed antigens bound to the MHC. This leads to massive stimulation of host T cells and release of cytokines, which mediate the systemic effects of S. aureus enterotoxin.
Exfoliative toxins of S. aureus are associated with the staphylococcal scalded-skin syndrome, in which cells in the granular layer of the epidermis detach from each other and form skin blisters.
Candida albicans is the most common human fungal infection. C. albicans is part of the normal floor of the skin, mouth, and GI tract. C. albicans infections vary from superficial lesions in healthy persons to disseminated infections in neutropenic patients.
Candida grow as yeast forms which are tandem arrays of elongated forms without hyphae (pseudohyphae), and true hyphae with septae. All may be mixed together in the same tissue, and all are stained with Gram, periodic acid-Schiff, or methenamine silver. Candida grows best on warm, moist surfaces and so frequently causes vaginitis (particularly during pregnancy), diaper rash, and oral thrush. Dishwashers, diabetics, and burn patients are also particularly susceptible to superficial Candidiasis. Chronic Mucocutaneous candidiasis occurs in persons with AIDS, in individuals with inherited or iatrogenic defects in T cell-mediated immunity, and in persons with polyendocrine deficiencies (hypoparathyroidism, hypoadrenalism, and hypothyroidism). Severe disseminated candidiasis is associated with neutropenia secondary to chronic granulomatous disease, leukemia, anticancer therapy, or immunosuppression after transplantation. Candida is directly introduced into the blood by intravenous lines, catheters, peritoneal dialysis, cardiac surgery, or intravenous drug abuse. Although the course of candidal sepsis is less rampant than that of bacterial sepsis, disseminated Candida eventually causes shock and DIC.
Candida has numerous molecules on its surface that mediate its adherence to host tissues, including (1) a receptor homologous to the human CR3 integrin, which binds RGD groups on C3bi, fibrinogen, fibronectin, and laminin; (2) a lectin that binds sugars on epithelial cells; and (3) mannose-containing proteins that bind to lectin-like molecules on epithelial cells. Other virulence-associated factors include a secreted aspartyl proteinase, which may be involved in tissue invasion by degrading extracellular matrix proteins, and secreted adenosine, which blocks neutrophil oxygen radical production and degranulation.
The present invention is directed to a method and pharmaceuticals for treating HIV and secondary infection. One aspect of this invention involves the use of one or more polypeptides with an amino acid sequence including KPV, MEHFRWG (SEQ ID NO: 1), HFRWGKPV (SEQ ID NO: 2), or SYSMEHFRWGKPV (SEQ ID NO: 3) for treatment of HIV. HIV is accompanied by infections, inflammation or both. In one preferred embodiment of the invention, the one or more polypeptides are used for treatment of HIV itself via medication taken orally or parenterally. In another preferred embodiment of the invention, the treatment is for secondary infections arising from Staphylococcus aureus and Candidia albicans and can be taken either orally or parentally. In another preferred embodiment of the invention, treatment is carried out by local application of the polypeptides through a carrier onto the site of S. aureus or C. albicans infection.